Substance-P is neuropeptide consisted of 11 amino acids the tachykinin family that is expressed in sensory neurons, macrophages, eosinophils, endothelial cells, and corneal cells such as epithelial cells and keratocytes as well as granulation tissue. Several reports have suggested implication of Substance-P in neuro-immune communication on hematopoietic modulation. The bone marrow stroma was innervated by Substance-P nerve fibers and Substance-P stimulates marrow stromal cells through their surface receptor NK-1 to produce the stem cell factor and interleukin-1, which may be favorable for hematopoietic stimulation as feeders. However, the role of Substance-P in the systemic MSC mobilization and MSC repopulation in the bone marrow has not been reported yet.
A wound itself creates a unique and specific microenvironment that is composed of growth factors, cytokines, neurohormones, and extracellular matrix, all of which are secreted from the neighboring cells, blood born cells, and sensory neurons. Some factors in the wound microenvironment may last sufficiently long to be diffused into the peripheral blood, and in turn affect the stem cells in the bone marrow, to induce mobilization of the bone marrow cells into peripheral blood, supply of the bone marrow cells into the wound site, and participation of the bone marrow cells in the wound healing.
Recent cell transplantation experiments with bone marrow stem cells and cultured MSCs show that they are involved in the tissue repair of lung, gastrointestinal tract, and infarcted myocardium. However, in a normal physiological state without any wound, MSCs are detected in tissues such as fat tissue and pterygium except the bone marrow, but barely in the peripheral blood. Therefore, it is believed that there may be a certain system to mobilize MSCs from the bone marrow into other peripheral tissue during tissue repair and pathological progression.
The cornea is consisted of transparent, avascular and heavily innervated tissue, whose integrity may be broken in case of corneal damage and disease thereof. A corneal wound stimulates lateral movement of the corneal epithelial cells most likely provided by the limbal stem cells, infiltration of the inflammatory cells, and neovascularization in the wound stroma, all of which may be stimulated by the unique corneal wound microenvironment. Previous reports suggest that corneal denervation is a cause of substantial delay in the wound healing process, and the lower level of Substance-P in diabetic patients than non-diabetic patients is also a cause of delayed re-epithelialization and delayed healing. Since the cornea surface is extensively innervated by trigeminal ganglion neurons, and endogenous Substance P is expressed in the corneal epithelial cells and keratocytes, it is expected for Substance P to involve in the wound microenvironment and participate in cornea repair.